2-chloro-{66 1,4-steroids

ABSTRACT

WHEREIN R1 is hydrogen or methyl, R2 is hydrogen, hydroxyl or esterified hydroxyl, X is fluorine, chlorine or methyl, Y is hydrogen or halogen, and Z is halogen having the same or a smaller atomic weight then Y, a Beta -position hydroxyl and in the case where Y is hydrogen, an Alpha -position hydroxyl.   Novel 2-chloro- Delta 1,4-steroids having the formula

United States Patent Laurent et ai. 1 1 July 18, 1972 s41 2-CHLOR0-Al,4-STEROIDS 571 mm [72] Inventors: Henry Laurent; Knrl Heinz Kolb; Rudolf Novel 2-chloro-AL4-steroids having the formula Wkchert, all of Berlin, Germany [73] Assignee: Scherlng Aklienglselkchnlt, Berlin and Berg Kamen, Germany 221 Filed: April 22, 1970 [2|] Appl. No.: 30,934

[30] Foreign Application Priority Dita April 23, 1969 Germany............ .........P 19 21 397.9 April 23, 1969 Germany..... ...P 19 21 393.0 June 19, I969 Germany ..P 19 31 508.3 H1

52 us. (:1 zen/239.55, 260/397.45, 424/243 'F" is "Ydmflm 9' methyl. is l 8 hydroxyl or 511 1111. C1 ..co11s9/3z estenfi hydmy" X methyl Y is [58] Field Search ..260/239.55, 391.45; hydmflfll P a m and Z is haloaen ing th same or a Machine searched steriods smaller atomlc weight then Y. a fi-position hydroxyl and in the Attorney-Michael S. Striker case where Y is hydrogen, an a-position hydroxyl.

37 Clalrm, No Drawings Z-CHLORO-A l ,4-S'IEROIDS The instant invention relates to a novel series of 2-chloro- A"-steroids having pharmacological activity.

The 2-chloro-A"-steroids of the invention may be designated by the following formula:

CII2R2 wherein R,, X, Y and 2 have the same meaning as given above and R is hydrogen or an esterified group a chlorine atom in the presence of an inert polar solvent and thereafter subjecting the thusly recovered mixture consisting of the 1,2- dichloro-A'-compound and the Z-ChIOI'O-A -COIIIPOUMI to a chromatographic separation or treatment with a tertiary amine, and if desired the esteritied 2l-hydroxyl group can be saponified and then if desired re-esterifted, or

b. for the preparation of products where Y is a halogen atom treating a compound having the following formula:

CH R:

it wherein X and R are as above set out, 2 is an aor B-position hydroxyl group, R, is hydrogen or an esterified hydroxyl group and BA designates:

in the conventional manner for splitting oil the l l-position hydroxy] group under simultaneous splitting off if necessary of the present I-position chlorine atom as hydrogen chloride and then adding halogen, hypochlorous or hypobromous acid onto the formed A' -double bond, and if desired convening the resultant 9-halogen-l l-hydroxy compound into the 9,l lflepoxide and thereafter cleaving the epoxide ring with hydrogen fluoride, and also if desired saponit'ying the esterified Zl-hydroxy group and if further desired re-esterifying the same.

For the esterification, there are suitable the conventional acids and acid derivatives used in steroid chemistry. Preferred acids are organic carboxylic acids containing up to l5 carbon atoms. The acids can be unsaturated, branched, polybasic or conventionally substituted, as for instance with hydr0xy-,ox0-, or amino groups or with halogen atoms, There are suitable for use in the process of the invention cycloaphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids which can also be substituted. instances of suitable acids are for example formic acid, acetic acid, propionic acid, butyric acid, valerianic acid, caproic acid, enanthic acid, undecylic acid, trimethylacetic acid, diethylacetic acid, t-butylacetic acid, phenylacetic acid, cyclopentyl propionic acid, oleic acid, lactic acid, mono-, diand trichloracetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, succinic acid, adipic acid, benzoic acid, nicotinic acid, etc. Further, there may be advantageously used the common inorganic acids such as sulfuric and phosphoric acid.

For the preparation of water soluble products, the substituted aminoacylates such as diethylaminoand piperidino acetate can be converted into acid addition salts, dicarboxylic acid semi-esters and the sulfuric acid and phosphoric acid esters into the alkali metal salts.

The feasibility of the process of the invention according to procedure (a) is most surprising since it is known that the l I ,8 hydroxy group of prednisolone must be converted into the trifluoroacetoxy group before the chlorination (U.S. Pat. No. 3,232,835) if a simultaneous oxidation of the llB-hydroxy group into the l l-keto group is to be avoided. In the process of the invention there are employed starting materials which are substituted in the 6-position which makes unnecessary any protection of the l l B-hydroxy group.

The chlorination in the procedure (a) of the invention can be carried out with chlorine or with chlorine containing compounds capable of liberating positive and negative chlorine in an inert polar solvent. Reagents which liberate positive chlorine are illustrated for example by chlorosuccinimide and chloroacetamide. As reagents which liberate negative chlorine, there may be mentioned hydrogenchloride and alkali metal chlorides.

The procedure as designated (a) is carried out in accordance with the invention in an inert polar solvent. As solvents for this purpose, there may be used lower carboxylic acids such as acetic acid and propionic acid, cyclic ethers such as tetrahydrofuran and dioxan, lower alltylethers, for example diethylether and dibutylether, lower alkylnitriles, as for instance acetonitrile and propionitrile, and the like.

The chlorination is preferably carried out at temperatures between 20 and 50C.

The chlorination products which are isolated are mixtures of la,2fl-dichloro-A-l l-hydroxyand 2-chloro-A"-l lhydroxy-steroids. They are separated for example by chromatography. The primary recovered 1,2- dichloro-compound can however be completely converted into the Z-monochloro- A'-compound by reaction with a tertiary amine. Examples of tertiary amines which can be used for this purpose, i.e., for the splitting off of hydrogen chloride include N,N-dialkyl-aniline, triethylamine, pyridine, quinoline, collidine, lutidine, picoline and the like. Also in the saponification of the 2l-ester, the labile dichloro-compounds are converted into the monochloro compounds.

The process variation (b) is carried out in the conventional manner. One possibility for splitting off water from the 9,l lposition lies in reacting the l Lhydroxy-Z l-acetoxy-steroid with an acid chloride, as for instance methanesulfonic acid chloride, in the presence of an organic base such as pyridine and dimethylformamide under heating of the mixture. if l,2-

dichlorosteroids are used as starting materials, a simultaneous splitting off of hydrogen chloride from the 1,2 position takes place to produce the corresponding 2-chloro-A-steroid.

The addition of halogen to the A""-doub1e bond according to process variation (b) can be carried out by a large number of procedures. For instance, halogen, that is chlorine or bromine or mixed halogenes as for example, in chlorornonofluoride or bromomonochloride, or halogen in the form of a polyhalogenide, for example, potassium triiodide or iodobenzenedichloride can be directly added on to the double bond.

A particularly good method for carrying out the halogen addition is to provide a positive and negative halogen for effecting the A""-addition. lnstances of reagents containing positive halogen include for example, halogensuceinimide, halogenacetamide or the halogens themselves. Examples of reagents for supplying negative halogen are the hydrogenhalides and the alkali metal halogenides, in particular lithiumhalogenide, for instance lithiumchloride and lithium-bromide.

The addition of the halogen to the d -double bond of the steroid takes place so that the positively charged halogen adds on at the 9-position and the negatively changed halogen adds on at the l l-position of the molecule. The halogen atom in the 9-position must have an atomic weight which is not less than that of the halogen atom in the ll-position because of the known differences in electronegativities of the halogens. The halogen addition at the A"-double bond is preferably carried out at temperatures between 75 and +50C.

The addition of hypohalogeneous acids to the A-duble bond of the steroid is carried out using the known methods. A preferred method comprises treating the A""-double bond with a reagent which in the presence of water and in an acid reaction medium liberates hypochlorous or hypobromous acid, and in particular with halogen cation forming reagents such as for example, dibromomethyl-hydantoin, N-halogenacylamide, preferably N-chloroor N-bromoacetamide or N- halogenacylimides, particularly N-brorno or N-chloro-succinimide.

If the desired final products are 9a-fluoro compounds, then following the addition of the hypohalogenite to the 9,1 1- double bond, the Qa-bromo- (or chloro-) 1 lB-hydroxy group can in the known manner as for instance by treatment with basic reagents such as NaOH,KOH,K,CO potassium acetate, pyridine and the like, and preferably at elevated reaction temperature, be converted into a 9,1 l-oxido ring. The epoxy group can thereafter by treatment with hydrofluoric acid be converted into the l lfi-hydroxy-Qa-fluorogroup.

The novel compounds of the invention when employed in the vase-constriction test on male subjects demonstrated after local application a marked inflammation inhibiting activity. The results of these tests are set out in a table which follows and in which Examples ll to V1 are compounds of the inven' tion and are compared with the known compound oer-fluoro- I 13,21-dihydroxy-16a-methyl-l,4-pregnadiene3,20-dione.

The vasoconstriction test as reported in the table was carried out as follows: The backs of male subjects 18-38 years of age were subjected to 20 repeated scrapings with a 2 cm wide Tesafilm which served to cut up the Stratumcorneum and produce a marked hyperemia. There was then applied to designated 4 on: size areas of the stripped backs under identical conditions about 50 mg of a water/oil ointment base which contained 0.1%, 0.01% or 0.001% of the test substance. The backs of the subjects were photographed at designated time intervals using Kodak-color film. The evaluation of the hyperemia and vasoconstriction were made by converting the color of each skin area as recorded on the Kodak-color film into brightness values. Differences in brightness of the color films are by means of a diaphragm projected on an interference filter. As a brightness indicator there is used a secondary electron multiplier and the determination of the color value carried out by measuring the anode current of the secondary multiplier.

in order to evaluate the vasoconstriction, the same being representative of the syndrome of inflammation inhibition and relative to the onset of activity, degree of activity and duration of activity, the color values of the untreated and of the treated stripped skin were determined and compared with the color value of the normal skin, wherein the color value of the normal skin was set at 100 and of the untreated stripped skin at zero. Low-grade, average and high-grade vasoconstriction are designated by values between zero and 100.

TABLE 1 Compound DosageObservation time in X in hours 1 ba-fluoro-l 1B, 2ldihydroxy- 0.1 5 35 65 100 16a-methyl-1,4-pregnadiene- 0.01 0 20 40 50 3,20-dione 0.001 0 20 40 55 ll 6a-lluoro-2-chloro-1 113,21- 0.1 10 55 90 100 dihydroxyl 6a-methyl- 1,4-pregnadiene-3,ZO-dione 0.01 5 35 100 111 6a-lluoro-2-chloro-l 13- 0.1 10 50 100 hydroxy-Z l-trimethylacetoxy lfia-methyl-l ,4-pregnadiene 0.01 10 40 3,20-dione 1V 6a.)a-difluoro-2-chloro- 0.l 20 70 100 llfl-hydroxy-Zl-acetoxy- 0.01 l5 75 100 l6a-methyll ,4-pregnadiene- 0.001 5 30 80 100 3,20-dione V 6a-fluoro-2,9-dichloro-l la- 0.l 10 45 100 hydroxy-Z l-acetoxy- 16w 0.01 10 30 75 100 methyl-1,4-pregnadiene- 0.001 0 25 40 80 3,20-dione Vl 6a-fluoro-2,9,l 1B-trichloro- 0.] I0 30 60 100 2 l -acetoxylba-methyll ,4- 0.01 5 30 50 90 pregnadiene-3,20-dione The data in the table unequivocably establishes that the use of the compounds of the invention produced an early onset of action and the maximum effect was reached sooner than with the comparison compound.

The novel compounds of the invention can be formulated with the conventional additives and carriers to produce compositions suitable for use by local application in the treatment of contact dermatitis, eczema of various types, neurodermatitis, erythematodes cutaneous, psoriasis, Lichen ruber planus, burns (grade 1), pruritus vulvae and ani, Rosacea, and verrucosus and by oral administration in the treatment of acute or chronic polyarthritis, neurodermititis, asthma, bronchitis, hay fever and the like.

The following Examples are given to further illustrate the invention, but are not to be taken as limitative of the scope thereof.

EXAMPLE 1 A solution of 25.0 g. oa-fluoro-l lB-hydroxy-Zl-acetoxy-l a-methyl-1,4-pregnadiene-3,ZO-dione in ml tetrahydrofuran and 250 ml methylenechloride was reacted at l0C with 50 g N-chloro-succinimide and 62.5 ml HCl saturated dioxan. After 10 minutes the reaction mixture was poured into water, extracted with methylene chloride, the extract washed with sodium sulfite, sodium hydrogencarbonate solution and water, dried over sodium sulfate and the solvent evaporated ofi. The crude product was chromatographed on silica gel. 1.3-1.9 percent. Acetonemethylene-chloride eluted 5.95 g 6a-fluoro- 1a,2/3-dichloro-l l B-hydroxy-Z l -acetoxyl 6a-methyl-4- pregadiene-3,20-dione having a melting point of l77l 78C (out of acetone-hexane); [11],, +l20(chloroform UVze l3,100 (methanol). 1.9-2.8 percent acetonemethylene-chloride eluted 9.4 g 6a-fluoro-2-chloro-l lfihydroxy-Z 1 -acetoxyl 6a-methy1- l ,4-pregnadiene- 3,20-dione having a melting point of 207-209C; [01],, +86 (chloroform). uv=@,,,= 14,800 (methanol).

l .0 g 6a-fluoro-l l B-hydroxy-Z l -acetoxyl a-methyll ,4- pregnadiene-3,20-dione dissolved in 10 ml tetrahydrofuran and 10 ml dimethylformamide was reacted with 20 ml propionic acid containing 5 percent dissolved chlorine and allowed to stand for 3 hours at room temperature. The reaction mixture was poured into water and the precipitated material separated out and dissolved in 25 ml pyridine. After 24 hours the pyridine solution was poured into ice water. The separated product was chromatographed on silica gel. 21-26 percent. Acetone-pentane eluted 405 mg 6a-tluoro-2-chloro-l IB- hydroxy-2 l -acetoxyl 6a-methyll ,4-pregnadiene-3,20-dione having a melting point of 2072l lC (out of acetone-hexane).

EXAMPLE 3 A solution of [0.0 g oa-tluoro-l lfl-hydroxy-Zl-trimethylacetoxy-l6a-methyl-l,4-pregnadiene-3,20-dione in 50 ml tetrahydrofuran and 100 ml methylenechloride was reacted at C with 20 g N-chloro-succinimide and 20 ml HCl saturated dioxan. After 20 minutes the reaction mixture was poured into water, the precipitated product isolated and dissolved in 100 ml pyridine. The solution was heated for 2 hours at 60C and then poured in l-lCl containing ice water. The mixture was ex tracted with methylenechloride, washed with dilute hydrochloric acid, sodium hydrogen carbonate and water, dried over sodium sulfate and the solvent evaporated off. The crude product was chromatographed on silica gel. 7-9 percent Acetone-methylene chloride eluted 7.] g 6a-fluoro-2-chlorol lB-hydroxy-2 l -trimethylacetoxyl 6a-methyll ,4- pregnadiene-3,20-dione having a melting point of l56-l58C (out of acetone-hexane).

EXAMPLE 4 l l g oa-fluorola,2fi-dichloro- I lB-hydroxy-Z I -acetoxyl 6 a-methyl-4-pregnene-3,20-dione were dissolved in ll ml methylene chloride and 17 ml methanolic 0.2 N KOl-l solution were then introduced. After 20 minutes, the reaction mixture was diluted with methylene chloride and washed till neutral with water. The organic phase was dried and concentrated and the residue chromatographed on silica gel. 7.5-l2.8 percent Acetone-methylenechloride eluted 670 mg 6a-fluoro-2- chloro- 1 I82 I -dihydroxyl 6a-methyll ,4-pregnadiene-3,20 dione having a melting point of 2l l2 l 5C (out of methylene chloride-hexane), [01],, +66(chloroform). 0V1, l4,800 (methanol).

EXAMPLE 5 2.0 g 6a-fluoro-2-chloro- I lB-hydroxy-Z I-acetoxy- 1 6amethyl- I ,4-pregnadiene were saponiied as described in Example 4. The crude product was crystallized out of acetone-hexane. The yield amounted to 1.32 g 6a-fluoro-2-chloro-I 1,6,21- dihydroxyl oa-methyll ,4-pregnadiene-3,20-dione having a melting point of 2 I0-2 I 3C (out of acetone-hexane EXAMPLE 6 Three hundred mg 6a-fluoro-2-chloro-l1B,2l-dihydroxylfia-methyl-l,4-pregnadiene-3,20-dione were in 1.2 ml pyridine acetylated with 0.6 ml acetanhydride by allowing such mixture to stand for 45 minutes at room temperature. Following precipitation with water, the product was separated off with suction, washed, dried and crystallized out of acetonehexane. There was recovered 255 mg 6a-tluoro-2-chloro-l IB- hydroxy-Z l-acetoxyl oa-methyll ,4-pregnadiene-3,20-dione having a melting point of 214-2l5C; [11],, +86 (chloroform). UVze l4,800 (methanol).

EXAMPLE 7 A solution of 1.2 g 6a-tluoro-2-chIoro-l 1,6,2 l-dihydroxyl 6 a-methyl-l,4-pregnadiene-3,20-dione in 4.8 ml pyridine was reacted with 2.4 ml butyric acid anhydride and allowed to stand for 24 hours at room temperature. The mixture was poured into icewater, the crude product filtered off with suction, dissolved in methylene chloride and the solution treated with steam. The residue from the steam distillation was isolated and chromatographed on silica gel 2.8-4.3 percent Acetone-methylene-chloride eluted 865 mg 6a-fluoro-2- chloro- I lB-hydroxy-2 l -butyryloxyl 6a-methyll ,4- pregnadiene-3,20-dione having a melting point of 9|-93C (out of acetone-hexanehlal =+83(chloroform). UV:e,.,== 14,100 (methanol).

EXAMPLE 8 A solution of l .2 g 6a-lluoro-2-chIoro-l lB,2l-dihydroxyl 6 a-methyll ,4-pregnadiene-3.20-dione in 12 ml methylenechloride was reacted with 2.4 ml trimethylacetic acid anhydride and 6 ml 20 percent aqueous soda lye. The mixture was refluxed under intensive stirring, thereafter diluted with methylene chloride and washed till neutral with water. Following drying and evaporation of the solvent, there was recovered an oil which was chromatographed on silica gel. 7.0-9.5 percent Acetone-methylene chloride eluted [.21 g 6a-fluoro-2- chlorol l B-hydroxy-Z l-trimethylacetoxyl oa-methyll ,4- pregnadiene-3,20-dione having a melting point of l57"- l 58C (out of acetone-hexane); (0:1,, +82(chloroform). UV:e, =l 4,100 (methanol).

EXAMPLE 9 A solution of 1.0 g 6a-fluoro-2-chloro-l lB,2l-dihydroxyl 6 a-methyl-l,4-pregnadiene-3,20-dione in 4 ml pyridine and 2 ml caproic acid anhydride was allowed to stand for 24 hours at 25C. The solution was then poured into ice water and extracted with methylene chloride. The extract was washed with dilute hydrochloric acid, sodium hydrogencarbonate solution and water, dried and chromatographed on silica gel. 7-l0 percent Acetone-pentane eluted 833 mg 6a-fluoro-2-chloro-l l B- hydroxy-2 l -hexanoyloxyl 6a-methyll ,4-pregnadiene-3 ,20- dione as a colorless, viscous oil. [a], +(chloroform) UV:c, =l 4,600 (methanol) EXAMPLE [0 7.0 ml pyridine was cooled down to l$C and reacted with 0.4 ml freshly distilled sulfur trioxide. At a temperature of about 0C, 3.0 g 6a-lluoro-2-chloro-l lB,2l-dihydroxy-l6amethyl-l,4-pregnadiene-3,20-dione was introduced into the mixture and stirring continued for 1 hour whereupon the temperature increased from 0C to room temperature. The mixture was diluted with 65 ml water, brought to a pH of 8.6 with 22.2 ml of soda lye and repeatedly extracted with methylenechloride for removal of the pyridine. The aqueous phase was evaporated in vacuo at 40C and the residue digested with methanol. The undissolved sodium sulfate was filtered off and the methanol evaporated. The residue was taken up in a small amount of methanol and crystallized by the addition of ether thereto. There were recovered 2.52 g sodium-( 6a-fluoro-2-chlorol l fi-hydroxy-3,20-dioxol 60- methyl-l,4-pregnadiene-2l-ylJ-sulfate having a melting point of l8l-l85C. [a],,= +65'(methanol). UV: e,,,.,= 14.800 (methanol).

EXAMPLE I l l .4 g 6a-fluoro-2-chloro-l lB,2l-dihydroxy-loat-methyll,4pregnadiene-3,20-dione in 2.8 ml pyridine were reacted with 1.4 ml valerianic acid anhydride and the reaction mixture stirred for 3 hours at room temperature. The reaction mixture was then subjected to steam distillation. The reaction product was isolated from the distillation residue with methylenechloride and crystallized out of acetone-hexane. The yield amounted to 970 mg 6a-fluoro-2-chloro-l lB- hydroxy-Z l -valeryloxyl 6a-methyll ,4-pregnadiene-3.20- dione having a melting point of [QT-C. [41:1 +98 (chloroform). UVze- F 15,300 (methanol).

EXAMPLE 12 2.0 g 6a-fluoro-1la-hydroxy-Zl-acetoxy-l6a-methyl-l,4- pregnadiene-3,20-dione were dissolved in m1 tetrahydrofuran and 20 ml methylenechloride and reacted at 10C with 4.0 g N-chlorosuccinimide and 5.2 ml HCl saturated dioxan. After minutes, the reaction mixture was poured into water and extracted with methylenechloride. The extract was washed with sodium hydrogensulfitesodium hydrogencarbonate solution and water and after drying over sodium sulfate, evaporated. The residue was chromatographed on silica gel. -25 percent Acetone-hexane eluted 655 mg 6:!- iluoro-2-chloro-l la-hydroxy-Z 1 -acetoxy- 1 fia-methyl- 1 ,4- pregnadiene-B,20-dione having a melting point of 2l6-218.5 "C (out of acetone-hexane). [01],, +41 (chloroform). UV: e 15,800 (methanol).

EXAMPLE 13 A mixture of 5.9 g 6ailuoro-1a,2fi-dichloro-l lB-hydroxy- Zl-acetoxy-l6oz-methyl-4-pregnene-3,20-dione, 29.5 ml dimethylformamide, 5.9 ml pyridine and 2.95 ml methanesulfochloride was heated for 80 minutes under nitrogen. After cooling, the mixture was poured into water, the precipitated product isolated and chromatographed on silica gel. 2.2-3.6 percent Acetone-methylenechloride eluted 3.43 g 6a-fluoro-2 -chloro-2 l-acetoxyl 6a-methyll ,4,9(1 1 )-pregnatrienc-3,20- dione having a melting point of 161162C (out of acetonehexane); [01],, +116 (chloroform). UV: e 16,000 (methanol).

EXAMPLE 14 9.2 g 6a-fluoro-2-chloro-l lB-hydroxy-Zl-acetoxy-16amethyl-l,4-pregnadiene3,20-dione were reacted with methane-sulfochloride in dimethylformamide-pyridine as described in Example 13. The yield amounted to 7.65 g 60:- fluoro-2-chloro-2l-acetoxy-loa-methyl-l,4,9(1 l)- pregnatriene-3,20-dione having a melting point of 159-l 60C (out of acetone-hexane).

EXAMPLE 15 EXAMPLE 16 A solution of 8.5 g 6a-fluoro-2-chloro-21-acetoxy-16amethyl-l,4,9( l l )-pregnatriene-3,20-dione in 340 ml dioxane was reacted with 85 ml water, 8.5 g N-bromosuccinimide and 8.5 ml 70 percent perchloric acid. After 50 minutes, the reaction mixture was poured in sodium sodium sulfite containing ice-water and the precipitated product isolated. The yield of crude product amounted to l0.3g. 500 mg were crystallized out of methylenechloride-acetone-hexane and yielded 400 mg 6a-i'luoro-bq-chloro-9-bromo-1 lfi-hydroxy-Z l-acetoxy-lfia methyl- 1 ,4-preg-nadiene-3,20-dione having a melting point of l83-18$C(decomp.). [01],, +93(chloroform); UVI 13,300 (methanol).

EXAMPLE 17 9.8g 6a-tluoro-2-chloro-9-bromo-1 lfi-hydroxy-Zl-acetoxyloa-methyl-l,4-pregnadiene-3,20-dione were dissolved in 250 ml ethanol, reacted with 12.5 g potassium acetate and heated for 2 hours under reflux. The reaction product was isolated by water precipitation and then chromatographed on silica gel. 14-17 percent Acetone-pentane eluted 6.6g of crude product. Two hundred mg were crystallized out of acetonehexane and yielded mg 6a-fluoro-2-chloro-2l-acetoxy- 9,1 lB-epoxy- 1 fia-methyl- 1 ,4-pregnadiene-3 ,ZO-dione having a melting point of l40.5-l42C; [01],, +38(chloroform). UV: e 15,200 (methanol).

EXAMPLE 18 Nineteen ml dimethylformamide were reacted with 19 ml anhydrous hydrogen fluoride at -50C. 6.4g 6a-fluoro-2- chloro-2 l -acetoxy-9,1 lB-epoxy-16a-methyl-l ,4-pregnadiene- 3,20-dione were dissolved in the resulting mixture and the solution allowed to stand for 5 days at room temperature. It was then poured into 1,300 ml water which contained 130 g potassium hydrogen carbonate. The precipitated material was separated off with suction and dissolved in methylenechloride. the solution dried with sodium sulfate and evaporated. The residue was chromatographed on silica gel. 4.7-7.8 percent acetone-methylene chloride eluted 2.62 g 60,9-difluoro-2- chloro-l lB-hydroxy-Z l-acetoxy- 1 6a-methyll ,4- pregnadiene-3,20-dione having a melting point of 204205C (out of acetone-hexane); [01 +84(chloroform); uv.-e,,,= 16,200 (methanol).

EXAMPLE19 Four hundred 6a-fluoro-2,9-dichloro-l lfl-hydroxy-2 l acetoxy16a-methyl-l ,4-pregnadiene-3,20-dione were dissolved in 8 ml methylene chloride. 8 ml Methanolic 0.2N potassium hydroxide were then introduced into the solution and stirring at room temperature under nitrogen carried out for 10 minutes. The reaction mixture was diluted with methylene chloride, washed with water until neutral, dried and concentrated under vacuum. The residue was chromatographed. 1ll3.5percent acetone-methylenechloride eluted mg 6a-fluoro-2,9-dichloro-l 113,2 1 -dihydroxy-1 6o:- methyl-l,4-pregnadiene-3,20-dione having a melting point of 249-250C(from methylenechloride); [01],, +95 (chloroform); UV e 15,200 (methanol).

EXAMPLE 20 2.42 g 6oz,9-difluoro-2-ch1oro-1 lB-hydroxy-Zl-acetoxy- 16a-methyl-1,4-pregnadiene-3,20-dione were saponified with potassium hydroxide solution as described in Example 19. The crude product was chromatographed on silica gel. 22-27 percent acetone-hexane eluted 1.23 g 6a,9-difluoro-2chloro- 1 113,2 l-dihydroxyl6a-methyl-1,4-pregnadiene-3,20-dione having a melting point of -200C; [011 +63 (chloroform). UV: e 15,100 (methanol).

EXAMPLE 21 A solution of 927 mg 60:, 9-difluoro-2-chloro-l 13,21- dihydroxy-16a-methyl-l,4-pregnadiene-3,20-dione in 9.5 ml methylenechloride was reacted with 1.85 ml trimethylacetic acid anhydride and 4.6 ml 20 percent aqueous soda lye. The mixture was refluxed under intensive stirring, thereafler diluted with methylenechloride and washed until neutral with water. The solvent was evaporated off following drying over sodium sulfate and the residue chromatographed on silica gel. 8.8-10 percent Acetone-pentane eluted 840 mg 612,9- difluoro-2-ch1oro-1 lfl-hydroxy-Z 1 -trimethylacetoxy- 1 6amethyl-l,4-pregnadiene-3,20-dione having a melting point of l06-108C; [al +78 (chloroform); UV: e 16,200 (methanol).

EXAMPLE 22 A solution of 1.7g 6a-fluoro-2-chloro-2l-acetoxy-16amethy1-1,4,9(11)-pregnatriene-3,20-dione in 85 m1 concentrated acetic acid was reacted with 1.7g N-chlorosuccinimide, 8.5g lithiumchloride and 1.7 ml hydrogen chloride saturated dioxan. The mixture was stirred for 90 minutes at room temperature and then poured onto icewater containing sodium sulfite. The precipitated product was isolated and chromatographed on silica gel. 20-25 percent acetone-pentane eluted 5 14 mg 6a-fluoro-2,9-l Ifl-trichloro-2 l-acetoxy-l lid-methyll ,4-pregnadiene-3,20-dione having a melting point of 223-22 8C (from acetone-hexane); [011 +l 27(chloroform) UV: e 15,400 (methanol).

EXAMPLE 23 3.0 g Ga-fluoro-Z-chloro-Zl-acetoxyl 6a-methyll ,4,9( l l)- pregnatriene-Ii,20-dione and 6.0g N-chlorosuccinimide were dissolved in a mixture of 6 ml anhydrous hydrogen fluoride, 9 ml tetrahydrofuran and I2 ml methylenechloride at -50C. After 18 hours of reaction time. the reaction mixture at a temperature of 0C was poured into water that contained sodium hydrogen carbonate and sodium hydrogensulfite. The precipitated material was isolated and chromatographed on silica gel. l3-l percent acetone-pentane eluted 882 mg 6a,] 1 B-difluoro-2,9-dichloro-2 l-acetoxyl 6a-methyll ,4- pregnadiene-3,20-dione having a melting point of 22 l-224C (from acetone-hexane); [0:1 +8l( chloroform); UV: e, l4,800(methanol).

EXAMPLE 24 1.0 g 6a,9-difluoro-2-chloro-l l 3,2 l -dihydroxyl 601- methyl-1,4-pregnadiene-3,20-dione in 2 ml pyridine was reacted with 1 ml valerianic acid anhydride and the reaction mixture stirred for 3 hours at room temperature. Reaction mixture was then subjected to steam distillation. The product was isolated from the steam distillation residue with methylenechloride and chromatographed on silica gel. 9-30 percent Acetone-pentane eluted 950 mg 60,9-difluoro-2- chloro-l lB-hydroxy-2 l-valeryloxyl 6a-methyll ,4- pregnadiene-J,20-dione having a melting point of l64-l65C (from acetone-hexane); [01],, =+9l( chloroform UV: e I 6,100 (methanol).

EXAMPLE 25 3 5 g 6a-fl uoro-2,9-dichloro-l 15,2 l-dihydroxy! 6amethyl-l,4-pregnadiene-3,20-dione were reacted with valerianic acid anhydride as described in Example 24. The crude product was chromatographed on silica gel. 30 percent Acetone-pentane eluted l.96 g 6a-fluoro-2,9-dichloro-l1B- hydroxy2 l-valeryloxyl 6a-methyll ,4-pregnadiene-3,20- dione having a melting point of l97l99C (out of acetonehexane). [0],, +ll0 (chloroform); UV: e 15,400 (methanol).

EXAMPLE 26 5.7 ml pyridine were cooled down to l5C and then reacted with 0.25 ml freshly distilled sulfur trioxide. At about 0C, there were introduced into the reaction mixture, l.78g 6a,9-difluoro-2-chloro-l lfi,2 l -dihydroxyl oa-methyll ,4- pregnadiene-ZLZO-dione and stirring continued for 1 hour whereby the temperature of the mixture increased to room temperature. The mixture was then diluted with 40 ml water, the pH adjusted to 8.6 with l6.9 ml lN soda lye and the pyridine removed by repeated extraction with methylenechloride. The aqueous phase was evaporated in vacuo at about 40C and the residue digested in methanol. The undissolved material was filtered off and the solvent evaporated. The residue was taken up in a small amount of methanol and brought to crystallization by the addition of ether. The yield amount-ed to 1.32 gsodium-( 6a,9-difluoro-2- chloro-l l B-hydroxy-3,20-dioxol oa-methyl-l ,4-pregnadiene- 2l-yl)-sulfate having a melting point of l90-l94C; [a],,"= +47 (methanol); UV: e =l 4,900 (methanol).

EXAMPLE 27 1.9 g 6a-fluoro-2,9-dichloro-l IB,2 l-dihydroxy- 1 6(3- methyl-l .4-pregnadiene-3,20-dione were reacted as described in Example 26. The yield amounted to 820 mg sodium-(6afluoro-2,9-dichlorol l fihydroxy-S ,ZO-dioxol oa-methyll ,4- pregnadiene-Zl-yl) sulfate having a melting point of l92'-l97 C; [a],,--- +66( methanol); UV: e, l3.500(methanol).

EXAMPLE 28 4.0 g 63,] l fl-difluoro-ZS-dichloro-Z l -acetoxyl 6a-methyll,4-pregnadiene-3,20-dione were saponified with potassium hydroxide solution as described in Example l9. Following crystallization out of acetone/hexane, l.5 g 601,1 lfi-difluoro- 2,9-dichloro-2 l -hydroxy-l 6fi-methyll .4-pregnadiene-3,20- dione having a melting point of 236-239C were recovered. lul =+95 (chloroform); UV: e, I 5,200 (methanol).

EXAMPLE 29 1.90 g 6a,l lfl-difluoro-2,9-dichloro-2 l-hydroxy-l 6amethyl-l,4-pregnadiene-2.20-dione were esterified with valerianic acid as described in Example 24. The crude product was chromatographed. 6-8 percent Acetone/pentane eluted l .33 g 601,1 1 B-difluoro-2.9-dichIoro-2 l -valeryloxy- I 601- methyl-l,4-pregnadiene-3,20-dione having a melting point of 66-67C (out of acetone/hexane). [011 (chloroform) UV: e, I4, I 00 (methanol) EXAMPLE 30 2.0 g 60:, l l fl-difl uoro-2,9-dichloro-2 l-hydroxy-l 6B- methyl-l ,4-pregnadiene-3,20-dione were esterified with trimethylacetic acid as set out in Example 2 l. The crude product was chromatographed. 6-8 percent Acetone/pentane eluted l.85 g 6a,! 1 fl-difluoro-2,9-dichloro-2 l trimethylacetoxyl 6a-methyll ,4-pregnadiene-3,20-dione having a melting point of l97-l98.5C (out of acetone/hexane). [01],, (chloroform). UV: e, 15,700 methanol).

Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can by applying current knowledge readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention and, therefore, such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claims.

What is claimed as new and desired to be protected by Letters Patent is set forth in the appended claims:

I. A 2-chloro-A'--steroid selected from the group of compounds having the following formulas:

CHrRI ZNW R CHDR:

R is hydrogen or methyl.

R, is hydroxyl or esterified hydroxyl,

X is fluorine, chlorine or methyl,

Y is halogen, and

Z is halogen having the same or a lesser atomic weight than Y, a fi-position hydroxyl and where Y is hydrogen Z can also be an a-position hydroxyl.

2. Compound according to claim 1 designated oa-fluoro-l a,2/3-dichloro-l l fl-hydroxy-Z l -acetoxyl 6a-methyl4- pregnene-3,20-dione.

3. Compound according to claim 1 designated 6a-flu0ro-2- chloro-l lfl-hydroxy-Z l-acetoxy-loa-methyll ,4 pregnadiene-3.20 dione.

{Compound according to claim l designated 6afluoro-2- chloro-l lfl-hydroxy-Z l -trimethylacetoxy-loa-methyll ,4- pregnadiene-3,20-dione.

5. Compound according to claim 1 designated 6a-fluoro-2- chloro-l 113,2l-dihydroxy-loa-methyl-l,4-pregnadiene-3,20 dione.

6. Compound according to claim I designated 6a-fluoro-2- chloro-l lBhydroxy-2l-butyryloxy-loa-methyll ,4: pregnadiene-320-dione.

7. Compound according to claim I designated 6a-fluoro-2- chloro-l lB-hydroxy'21-hexanoyloxy-l6a-methyl-1.4- pregnadiene-3,20-dione.

8. Compound according to claim 1 designated sodium-(6afluoro-2 chloro-l l fi-hydroxy-ILZtLdioxol 6a-methyl-l ,4- pregnadiene-Z l-yl )-sulfate.

9 Compound according to claim 1 designated 6a-fluoro2- chloro-l lB-hydroxy-Z l -valeryloxyl 6a-methyll ,4- pregnadiene3,20-dione.

l0. Compound according to claim I designated 6a-fluoro-2 -chloro-l la-hydroxy-Z l-acetoxyl 6a-methyll ,4- pregnadiene-3.20-dione.

11. a Compound designated 6a-fluoro-2-chloro 2 l-acetoxyl oa-methyll ,4.9( l l )-pregnatriene-3,ZO-dione.

12. Compound according to claim 1 designated (Ea-fluoro- 2,9-dichloro-l lB-hydroxy-Z l-acetoxyl oa-methyl-l .4- pregnadiene-B,20-dione.

13. Compound according to claim I designated 6a-fluoro-2 -chloro-9-bromo-l l B-hydroxy-Zl-acetoxyl6a-methyll ,4- pregnadiene-3.20-dione.

l4. a Compound designated 6a-fluoro-2-chloro-2l-acetoxy-9.l l/S-epoxyl 6a-methyll .4-pregnadiene-3,20-dione.

l5. Compound according to claim I designated 601,9- difluoro-Z-chloro-l lB-hydroxy-Z l-acetoxyl 6a-methyll .4- pregnadiene-J,20-dione.

16. Compound according to claim 1 designated 6a-fluoro- 2,9-dichloro-l Iii-2 l -dihydroxy-l oa-methyll ,4-pregnadiene- 3,20dione.

17. Compound according to claim I designated 60:,9- difl uoro-2-chloro-l 13,2 1 -dihydroxyl oa-methyll ,4- pregnadiene-3,20-dione.

18. Compound according to claim I designated 601,9- difluoro-Z-chloro-l lB-hydroxy-2 l -trimethylacetoxy-l 6amethyll ,4-pregnadiene-3,20-dione.

19. Compound according to claim 1 designated our-fluoro- 2 ,9,1 l B-trichloro-Z l -acetoxyl 6a-methyl-l ,4-pregnadiene- 3,20-dione.

20. Compound according to claim I designated 6al lfidifluoro-2,9-dichloro-2 l -acetoxy- 1 oo-methyll ,4- pregnadiene-S,20-dione.

Zl. Compound according to claim 1 designated 601,9- difluoro-Z-chloro-l l fl-hydroxy-2 l -valeryloxyl 6a-methyll ,4 -pregnadiene-3,20-dione.

22. Compound according to claim I designated 6a-fluoro 2.9-dichloro-l lB-hydroxy-2 l-valeryloxyl oa-methyll ,4- pregnadiene-3,20-dione.

23. Compound according to claim 1 designated sodium- (6a,9-difluoro-2-chloro-l l B-hydroxy-IXZO-dioxw l 60- methyll ,4-pregnadiene-2 l -yl )-sulfate.

24. Compound according to claim I designated sodium- (6a-fluoro-2,9-dichloro-l lB-hydroxy-3,20-dioxo-16amethyll ,4-pregnadiene-2 l-yl)-sulfate.

25. Compound according to claim 1 designated 601,1 IB- difluoro-2,9-dichloro-2 l-hydroxyl 6a-methyll ,4- pregnadiene-Ii,20-dione.

26. Compound according to claim I designated 6a,l 1B- difluoro-2,9-dichloro-2 l -valeryloxy l oa-methyll ,4- pregnadiene-3,20-dione.

27. Compound according to claim 1 designated 6a.l lB- difluoro-Z ,9-dichloro-2 l -trimethylacetoxyl oa-methyll ,4- pregnadiene-Il.20-dione.

28. A compound according to claim 1 having the formula wherein R R,, X, Y and Z are as defined in claim I 29. A compound according to claim I having the formula wherein X, R and R, are as defined in claim 1.

30. A compound according to claim 1 having the formula CHzR2 wherein X. R,, & R R, are as defined in claim I.

31. A compound according to claim I having the formula wherein R, is hydroxyl or esterified hydroxyl, Y is halogen and Z is halogen having the same or a lesser atomic weight than Y or a fi-position hydroxyl group.

32. A compound according to claim I having the formula (VII) wherein R X, Y and Z are as defined in claim 1 and R, is esterified hydroxyl in the presence of an inert polar solvent and separating the reaction mixture comprising l,2-dichloro- A -steroid and 2-chloro-A"-steroid into its components and converting said l,2-dichloro-A steroid into 2-chloro-A'--steroid by treatment thereof with a tertiary amine.

34. Process according to claim 33 wherein said separation is carried by chromatography.

35. Process according to claim 33 wherein said reaction mixture is subjected to treatment with a tertiary amine selected from the group consisting of N,N-dialkyl-aniline. triethylamine, pyridine, quinoline, collidine, lutidine and picoline.

36. Process for preparing a compound according to claim 1 wherein Y designates halogen which comprises treating a compound having the formula III) (III) wherein R, and X are as defined in claim 1, R is esterified hydroxyl and BA is so that the l l-position hydroxyl group will be split off as water and simultaneously the i-position chlorine atom is split off as hydrogen halide, thereafter adding on to the N -double bond, halogen or hypochlorous or hypobromous acid. wherein if the 2lhydroxyl group is esterified, the reaction product can be subjected to saponification to provide a 2l-free hydroxyl group.

37. Process according to claim 36 which comprises subjecting the 9-halogen-l l-hydroxy reaction product to epoxidation to form the corresponding 9,1 lflrepoxide and thereafter splitting the epoxide ring by addition of hydrogen fluoride.

i 1 1' i t 

2. Compound according to claim 1 designated 6 Alpha -fluoro-1 Alpha ,2 Beta -dichloro-11 Beta -hydroxy-21-acetoxy-16 Alpha -methyl-4-pregnene-3,20-dione.
 3. Compound according to claim 1 designated 6 Alpha -fluoro-2-chloro-11-hydroxy-21-acetoxy-16 Alpha -methyl-1,4-pregnadiene-3, 20-dione.
 4. Compound according to claim 1 designated 6 Alpha -fluoro-2-chloro-11 Beta -hydroxy-21-trimethylacetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 5. Compound according to claim 1 designated 6 Alpha -fluoro-2-chloro-11 Beta ,21-dihydroxy-16 Alpha -methyl-1,4-pregnadiene-3, 20-dione.
 6. Compound according to claim 1 designated 6 Alpha -fluoro-2-chloro-11 Beta -hydroxy-21-butyryloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 7. Compound according to claim 1 designated 6 Alpha -fluoro-2-chloro-11 Beta -hydroxy-21-hexanoyloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 8. Compound according to claim 1 designated sodium-(6 Alpha -fluoro-2-chloro-11-hydroxy-3,20-dioxo-16 Alpha -methyl-1,4-pregnadiene-21-yl)-sulfate.
 9. Compound according to claim 1 designated 6 Alpha -fluoro-2-chloro-11 Beta -hydroxy-21-valeryloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 10. Compound according to claim 1 designated 6 Alpha -fluoro-2-chloro-11 Alpha -hydroxy-21-acetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 11. a Compound designated 6 Alpha -fluoro-2-chloro-21-acetoxy-16 Alpha -methyl-1,4,9(11)-pregnatriene-3,20-dione.
 12. Compound according to claim 1 designated 6 Alpha -fluoro-2, 9-dichloro-11 Beta -hydroxy-21-acetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 13. Compound according to claim 1 designated 6 Alpha -fluoro-2-chloro-9-bromo-11-hydroxy-21-acetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 14. a Compound designated 6 Alpha -fluoro-2-chloro-21-acetoxy-9, 11 Beta -epoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 15. Compound according to claim 1 designated 6 Alpha ,9-difluoro-2-chloro-11 Beta -hydroxy-21-acetoxy-16 Alpha -methyl-1, 4-pregnadiene-3,20-dione.
 16. Compound according to claim 1 designated 6 Alpha -fluoro-2, 9-dichloro-11 Beta -21-dihydroxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 17. Compound according to claim 1 designated 6 Alpha ,9-difluoro-2-chloro-11 Beta ,21-dihydroxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 18. Compound according to claim 1 designated 6 Alpha ,9-difluoro-2-chloro-11 Beta -hydroxy-21-trimethylacetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 19. Compound according to claim 1 designated 6 Alpha -fluoro-2, 9,11 Beta -trichloro-21-acetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 20. Compound according to claim 1 designated 6 Alpha 11 Beta -difluoro-2,9-dichloro-21-acetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 21. Compound according to claim 1 designated 6 Alpha ,9-difluoro-2-chloro-11 Beta -hydroxy-21-valeryloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 22. Compound according to claim 1 designated 6 Alpha -fluoro-2, 9-dichloro-11 Beta -hydroxy-21-valeryloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 23. Compound according to claim 1 designated sodium-(6 Alpha , 9-difluoro-2-chloro-11 Beta -hydroxy-3,20-dioxo-16 Alpha -methyl-1,4-pregnadiene-21-yl)-sulfate.
 24. Compound according to claim 1 designated sodium-(6 Alpha -fluoro-2,9-dichloro-11 Beta -hydroxy-3,20-dioxo-16 Alpha -methyl-1,4-pregnadiene-21-yl)-sulfate.
 25. Compound according to claim 1 designated 6 Alpha ,11 Beta -difluoro-2,9-dichloro-21-hydroxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 26. Compound according to claim 1 designated 6 Alpha ,11 Beta -difluoro-2,9-dichloro-21-valeryloxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 27. Compound according to claim 1 designated 6 Alpha ,11 Beta -difluoro-2,9-dichloro-21-trimethylacetoxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 28. A compound according to claim 1 having the formula
 29. A compound according to claim 1 having the formula
 30. A compound according to claim 1 having the formula
 31. A compound according to claim 1 having the formula
 32. A compound according to claim 1 having the formula
 33. Process for preparing a compound according to claim 1 which comprises adding chlorine on to the Delta 1 - double bond of a compound having the formula
 34. Process according to claim 33 wherein said separation is carried by chromatography.
 35. Process according to claim 33 wherein said reaction mixture is subjected to treatment with a tertiary amine selected from the group consisting of N,N-dialkyl-aniline, triethylamine, pyridine, quinoline, collidine, lutidine and picoline.
 36. Process for preparing a compound according to claim 1 wherein Y designates halogen which comprises treating a compound having the formula
 37. Process according to claim 36 which comprises subjecting the 9-halogen-11-hydroxy reaction product to epoxidation to form the corresponding 9,11 Beta -epoxide and thereafter splitting the epoxide ring by addition of hydrogen fluoride. 